This invention relates to methods for treating fibrosis in subjects in need of such treatment.
Collagen is a fibril-forming protein which is essential for maintaining the integrity of the extracellular matrix found in connective tissues. The production of collagen is a highly regulated process, and its disturbance may lead to the development of tissue fibrosis. While the formation of fibrous tissue is part of the normal beneficial process of healing after injury, in some circumstances there is an abnormal accumulation of fibrous materials such that it may ultimately lead to organ failure (Border et al. (1994) New Engl. J. Med. 331:1286-1292). Injury to any organ leads to a stereotypical physiological response: platelet-induced hemostasis, followed by an influx of inflammatory cells and activated fibroblasts. Cytokines derived from these cell types drive the formation of new extracellular matrix and blood vessels (granulation tissue). The generation of granulation tissue is a carefully orchestrated program in which the expression of protease inhibitors and extracellular matrix proteins is upregulated, and the expression of proteases is reduced, leading to the accumulation of extracellular matrix.
Central to the development of fibrotic conditions, whether induced or spontaneous, is stimulation of fibroblast activity. The influx of inflammatory cells and activated fibroblasts into the injured organ depends on the ability of these cell types to interact with the interstitial matrix, which contains primarily collagens. The major cell surface collagen receptors are the xcex11xcex21 (VLA-1) and xcex12xcex21 (VLA-2) integrins. Both integrins have been implicated in cell adhesion and migration on collagen (Keely et al. (1995) J. Cell Sci. 108:595-607 and Gotwals et al. (1996) J. Clin. Invest. 97: 2469-2477); in promoting contraction of collagen matrices (Gotwals et al. (1996) J. Clin. Invest. 97: 2469-2477 and Schiro, (1991) Cell 67:403-410), and in regulating the expression of genes involved in the remodeling of the extracellular matrix (Riikonen et al. (1995) J. Biol. Chem. 270:1-5 and Langholz et al. (1995) J. Cell Biol. 131: 1903-1915). For example, when fibroblasts contact a collagen matrix, signaling through the xcex11xcex21 integrin down-regulates collagen I expression, while signaling through xcex12xcex21 up-regulates the expression of matrix metalloproteases (Langholz et al. (1995) J. Cell Biol. 131: 1903-1915).
Many of the diseases associated with the proliferation of fibrous tissue are both chronic and often debilitating, including for example, skin diseases such as scleroderma. Some, including pulmonary fibrosis, can be fatal due in part to the fact that the currently available treatments for this disease have significant side effects and are generally not efficacious in slowing or halting the progression of fibrosis (Nagler et al. 1996, Am. J. Respir. Crit. Care Med., 154:1082-86).
There is, accordingly, a continuing need for new anti-fibrotic agents.
In contrast to the trends in research in the field of anti-fibrotic therapy which has focused on upstream cytokine mediators of fibrosis, such as TGF-xcex2, we propose the use of antibody molecules comprising antigen binding regions derived from the heavy or light chain variable regions of an anti-VLA antibody, for use in anti-fibrotic treatment and specifically for treatment of pulmonary fibrosis.
The present invention provides a method of treating fibrosis in a subject. Specifically, the invention provides a method for treating fibrosis by administering to a patient a pharmaceutical composition containing an effective amount of an antibody molecule having antigen binding regions derived from the light and heavy chain variable regions of an anti-VLA antibody. In a preferred embodiment, the anti-VLA antibody is anti-VLA-1, -2, -3, -4, -5, and -6. In a most preferred embodiment, the invention provides a method for treating pulmonary fibrosis by administering to a patient a pharmaceutical composition containing an effective amount of an antibody molecule having antigen binding regions derived from the light and heavy chain variable regions of an anti-VLA-1 and anti-VLA-2 antibody.
The anti-VLA antibody can be selected from the group consisting of a human antibody, a chimeric antibody, a humanized antibody and fragments thereof. The anti-VLA antibody can be a monoclonal or polyclonal antibody.
The invention further provides a method for treating fibrosis in a subject that is a human or animal subject.
All of the cited literature in the preceding section, as well as the cited literature included in the following disclosure, are hereby incorporated by reference.